C1-4 alkanoylphenyl-esters of 5-hydroxy-PGI1, Δ4 -PGI1, and 4-oxo-PGI1 compounds

ABSTRACT

Acyl-substituted phenyl esters of prostacyclin-type compounds, for example the 4-acetylphenyl ester of prostacyclin (PGI 2 ) illustrated by the formula ##STR1## and including esters of the isomeric 6-hydroxy-PGI 1  and 6-keto-PGF 1 α compounds, said esters having pharmacological activity. Processes for preparing them and the appropriate intermediates are disclosed.

The present application is a divisional application of Ser. No. 933,329,filed Aug. 14, 1978, now issued as U.S. Pat. No. 4,180,657, on Dec. 25,1979.

The present invention relates to prostaglandin analogs for which theessential material constituting a disclosure therefor is incorporated byreference here from U.S. Pat. No. 4,180,657, issued Dec. 25, 1979.

I claim:
 1. An acid ester of a prostacyclin analog of the formula##STR2## wherein A is (1) --O-(oxa) or, when E is --CH₂ --, (2) --CH₂--O--, with --CH₂ bonded to R₈ wherein E is --CH₂ --or --CH₂ CH₂ --,wherein L₁ is(1) --(CH₂)_(n) -- wherein n is one to 5, inclusive, (2)--(CH₂)_(p) --CF₂ -- wherein p is one 2, 3, or 4, or (3) --(CH₂)_(v)--CH═CH-- wherein v is zero 1, 2, or 3, when M₂ is ##STR3##or L, is(1)-- (CH₂)_(n) --wherein n is one to 5 inclusive, (2)--(CH₂)_(p) --CF₂-- wherein p is 2, 3 or 4, or(3)--(CH₂)_(v) --CH═CH--wherein V is 1,2 or3, and M₂ is ##STR4## wherein ˜ indicates attachment in cis or transconfiguration wherein Q is ##STR5## wherein R₄ is hydrogen or alkyl ofone to 4 carbon atoms, inclusive, wherein R₁ is alkyl of one to 4 carbonatoms, inclusive, with the proviso that when R₁ is tert-butyl the--C(O)--R₁ group is in the 4-position, wherein R₈ is ##STR6## andwherein R₉ is ##STR7## wherein C₉ H₂.sbsb.] is alkylene of one to 9carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in thechain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ arehydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, beingthe same or different, with the proviso that one of R₅ and R₆ is fluoroonly when the other is hydrogen or fluoro and the further proviso thatneither R₅ nor R₆ is fluoro when Z is oxa (--O--);wherein Z representsan oxa atom (--O--) or C_(j) H_(z).sbsb.j wherein C_(j) H₂.sbsb.j is avalence bond or alkylene of one to 9 carbon atoms, inclusive, with oneto 6 carbon atoms, inclusive between CR₅ R₆ -- and the phenyl ring;wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbonatoms, inclusive, and s is zero, one, 2 or 3, with the proviso that notmore than two T's are other than alkyl and when s is 2 or 3 the T's areeither the same or different, and wherein X is(1) trans-CH═CH-- (2)cis-CH═CH-- (3) --C.tbd.C-- or (4) --CH₂ CH₂ --.
 2. (5S and5R)-5-Hydroxy-(6S)-PGI₁, 4-acetylphenyl ester, compounds according toclaim
 1. 3. (5S and 5R)-5-Hydroxy-(6R)-PGI₁, 4-acetylphenyl ester,compounds according to claim
 1. 4. (5S and5R)-5-Hydroxy-(15S)-15-methyl-(6S)-PGI₁, 4-acetylphenyl ester, compoundsaccording to claim
 1. 5. (5S and 5R)-5-Hydroxy-16,16-dimethyl-(6S)-PGI₁,4-acetylphenyl ester, compounds according to claim
 1. 6.(5R)-5-Hydroxy-13,14-didehydro-(6S)-PGI₁, 4-acetylphenyl ester, acompound according to claim
 1. 7. (5R)-5-Hydroxy-2,2-difluoro-(6S)-PGI₁,4-acetylphenyl ester, a compound according to claim
 1. 8.(5R)-5-Hydroxy-16-Phenoxy-17,18,19,20-tetranor-(6S)-PGI₁, 4-acetylphenylester, a compound according to claim
 1. 9. Trans-Δ⁴ -(6R)-PGI₁,4-acetylphenyl ester, a compound according to claim
 1. 10. Trans-Δ⁴-(6S)-PGI₁, 4-acetylphenyl ester, a compound according to claim
 1. 11.Trans-Δ⁴ -13,14-didehydro-(6R)-PGI₁, 4-acetylphenyl ester, a compoundaccording to claim
 1. 12. Trans-Δ⁴ -13,14-didehydro-(6R,15R)-PGI₁,4-acetylphenyl ester, a compound according to claim
 1. 13. Trans-Δ⁴-2,2-difluoro-16,16-dimethyl-(6R)-PGI₁, 4-acetylphenyl ester, a compoundaccording to claim
 1. 14. Trans-Δ⁴ -(15S)-15-methyl-(6R)-PGI₁,4-acetylphenyl ester, a compound according to claim
 1. 15. Trans-Δ⁴-16,16-dimethyl-(6R)-PGI₁, 4-acetylphenyl ester, a compound according toclaim
 1. 16. Trans-Δ⁴ -16,16-difluoro-(6R)-PGI₁, 4-acetylphenyl ester, acompound according to claim
 1. 17. Trans-Δ⁴ -13,14-didehydro-(6S)-PGI₁,4-acetylphenyl ester, a compound according to claim
 1. 18. Trans,trans-Δ²,Δ⁴ -(6S)-PGI₁, 4-acetylphenyl ester, a compound according toclaim
 1. 19. Trans, trans-Δ²,Δ⁴ -16,16-dimethyl-(6S)-PGI₁,4-acetylphenyl ester, a compound according to claim
 1. 20. Trans,trans-Δ²,Δ⁴ -13,14-didehydro-(6R)-PGI₁, 4-acetylphenyl ester, a compoundaccording to claim
 1. 21. Trans, trans-Δ²,Δ⁴ -(6R)-PGI₁, 4-acetylphenylester, a compound according to claim
 1. 22. Trans, trans-Δ²,Δ⁴-16,16-dimethyl-(6R)-PGI₁, 4-acetylphenyl ester, a compound according toclaim
 1. 23. Trans, trans-Δ²,Δ⁴ -16,16-difluoro-(6R)-PGI₁,4-acetylphenyl ester, a compound according to claim
 1. 24. An acid esterof a prostacyclin analog of the formula ##STR8## wherein Q is ##STR9##wherein R₄ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,wherein R₁ is alkyl of one to 4 carbon atoms, inclusive, with theproviso that when R₁ is tert-butyl the ##STR10## group is in the4-position, wherein R₈ is ##STR11## wherein R₉ is ##STR12## whereinC_(g) H₂.sbsb.g is alkylene of one to 9 carbon atoms, inclusive, withone to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- andterminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4carbon atoms, inclusive, or fluoro, being the same or different, withthe proviso that one of R₅ and R₆ is fluoro only when the other ishydrogen or fluoro and the further proviso that neither R₅ nor R₆ isfluoro when Z is oxa (--O--);wherein Z represents an oxa atom (--O--) orC_(j) H₂.sbsb.j wherein C_(j) H₂.sbsb.j is a valence bond or alkylene ofone to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusivebetween CR₅ R₆ -- and the phenyl ring; wherein T is alkyl of one to 4carbon atoms; inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ --wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero,one, 2 or 3, with the proviso that not more than two T's are other thanalkyl and when s is 2 or 3 the T's are either the same or different,wherein X is(1) trans-CH═CH-- (2) cis-CH═CH-- (3) -C.tbd.C-- or (4)--CH₂ CH₂ --, wherein w is one, 2, or 3, and wherein ˜ indicatesattachment in cis or trans configuration.
 25. (6R and 6S)-4-Oxo-PGI₁,4-acetylphenyl ester, compounds according to claim 24.